Pseudophosphatase MK‐STYX: the atypical member of the MAP kinase phosphatases

Abstract

The regulation of the phosphorylation of mitogen-activated protein kinases (MAPKs) is essential for cellular processes such as proliferation, differentiation, survival, and death. Mutations within the MAPK signaling cascades are implicated in diseases such as cancer, neurodegenerative disorders, arthritis, obesity, and diabetes. MAPK phosphorylation is controlled by an intricate balance between MAPK kinases (enzymes that add phosphate groups) and MAPK phosphatases (MKPs) (enzymes that remove phosphate groups). MKPs are complex negative regulators of the MAPK pathway that control the amplitude and spatiotemporal regulation of MAPKs. MK-STYX (MAPK phosphoserine/threonine/tyrosine-binding protein) is a member of the MKP subfamily, which lacks the critical histidine and nucleophilic cysteine residues in the active site required for catalysis. MK-STYX does not influence the phosphorylation status of MAPK, but even so it adds to the complexity of signal transduction cascades as a signaling regulator. This review highlights the function of MK-STYX, providing insight into MK-STYX as a signal regulating molecule in the stress response, HDAC 6 dynamics, apoptosis, and neurite differentiation. Abbreviations CH2, cell division cycle 25 phosphatase homology 2; DUSP, dual-specificity phosphatase; FBXW7, F-box and WD repeat domain containing 7; HDAC6, histone deacetylase 6; MAPK, mitogen-activated protein kinase; MKP, MAPK phosphatase; MK-STYX, MAPK phosphoserine/ threonine/tyrosine-binding protein; MTM, myotubularin; PTP, protein tyrosine phosphatase; STYX, phosphoserine/threonine/tyrosineinteracting protein.

The Roles of Pseudophosphatases in Disease

“…Pseudophosphatases of PTPs are widely accepted as having mutations within their signature active site motif (HCX 5 R) that renders them inactive [4,6,[10][11][12][13]. Mutations also may exist beyond the active site motif.…”

“…Pseudoenzymes' inability to perform catalysis categorizes them as atypical members within their superfamilies [1][2][3][4][5][6]. Over the past decade, the relevance of pseudoenzymes has been elevated and solidified as important signaling regulators.…”

“…Among these, pseudoenzymes, pseudokinases and pseudophosphatases provide the best examples of their molecular mechanisms. They serve as competitors, signal integrators, modulators, and anchors in cellular processes [5][6][7]. These modes of action and their roles in various cellular processes serve as an idea link for the roles of pseudoenzymes in pathologies and diseases.…”

The FEBS Journal in 2021: a sharp reminder that science really matters

“…We also published a Special Issue on 'Pseudoenzymes' (Fig. 2), edited by Colin Adrain (Queen's University, Belfast, N. Ireland) covering a diversity of topics highlighting the role of pseudoproteases, pseudokinases and pseudophosphatases, among other pseudoenzymes, in diverse biological processes ranging from cancer, inflammation, immunity and cell death [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. We are always very interested in hearing your proposals for Special Issues on cutting-edge topics of widespread interest; just email our editorial office with your proposal.…”

Pseudoenzymes: dead enzymes with a lively role in biology

“…This emphasizes that the study of dead enzymes is not simply an important discovery science pursuit, but also a potential conduit to pharmacologic modulation of currently undruggable pathways [9]. This theme is also emphasized in a review by Hinton [10]: that targeting pseudoenzymes, which often act as allosteric regulators of enzymes, may be a productive and novel way to block enzymatic activities during disease. Hinton highlights that the pseudophosphatase MK‐STYX, which is a catalytically inactive member of the MAP Kinase phosphatase family, is an important regulator of mitogen‐activated protein kinases signaling, a pathway associated with numerous conditions including cancer, neurodegenerative disorders, arthritis, and metabolic disease [10].…”